Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/06—Ring systems of three rings
  • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
  • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
  • C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/78—Separation; Purification; Stabilisation; Use of additives
  • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/78—Separation; Purification; Stabilisation; Use of additives
  • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
  • C07C45/82—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation

Definitions

• This invention relates to novel chemical compounds and their production. More particularly, this invention provides novel N-substituted cyclopentano [h]-1,2,3,4-tetrahydroisoquinolines, processes for producing the compounds, novel intermediates useful in making the compounds, and novel pharmaceutical compositions containing the compounds useful for effecting desirable pharmacological activity in animals.
• R and R 1 are hydroxy, lower alkoxy, lower alkanoyloxy or aryl-lower alkanoyloxy groups
• R 3 is hydrogen or a lower alkyl group
• R 4 is a lower alkyl, arylcarbonyl, aryl-lower alkyl, benzyhydryl-lower alkyl, lower alkanoyl, aryl-lower alkanoyl, benzhydryl-lower alkanoyl or benzhydrylcarbonyl group, and acid addition salts and quaternary ammonium salts of those compounds which form such salts.
• lower alkyl as used herein includes straight or branched chain alkyl groups having 1 to 8, and advisably 1 to 6, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, n-pentyl, isopentyl and n-hexyl.
• aryl as used herein includes the phenyl group and phenyl groups containing one to three nuclear substituents selected from (1) lower alkoxy groups such as the methoxy and ethoxy groups, (2) lower alkyl groups such as the methyl and ethyl groups, (3) halo groups including the chloro, bromo and fluoro groups, (4) the hydroxy group and (5) the amino group.
• benzhydryl includes the benzhydryl group and benzhydryl groups having, on one or both of the phenyl rings, one to three nuclear substituents selected from (1) lower alkoxy groups such as the methoxy and ethoxy groups, (2) lower alkyl group such as the methyl and ethyl groups, (3) halo groups including the chloro, bromo and fluoro groups, (4) the hydroxy group and (5) the amino group.
• lower alkanoyl includes saturated, monovalent groups derivable from monocarboxylic acids, including straight and branched groups having 1 to 8, and advisably 1 to 6, carbon atoms, such as formyl, acetyl, propionyl, ⁇ -methylpropionyl, butyryl and hexanoyl.
• lower alkanoyloxy includes saturated monovalent groups from monocarboxylic acids, including straight and branched groups, having 1 to 8, and advisably 1 to 6, carbon atoms such as formyloxy, acetoxy, propionyloxy and butyryloxy.
• R 5 and R 6 are lower alkoxy, and R 3 and R 4 have the assigned significance but R 4 has at least 2 carbons, all of which compounds come within Formula 1, can be produced by reacting a 5,6-di-lower alkoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline with an alkanoyl halide, an aryl-lower alkanoyl halide or a benzhydryl-lower alkanoyl halide to produce an ##EQU1## which is then reduced to the R 4 -N-5,6-dialkoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
• This process can be represented as follows: ##SPC4##
• R 3 , R 4 , R 5 have the previously assigned significance
• X is a reactive halo group such as the bromo and chloro groups and --CH 2 --R 7 equals R 4 .
• tetrahydroisoquinolines which can be used as starting materials in the described process are 5,6-dimehoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, 5,6-diethoxycyclopentano[h]-1,2,3,4-tetrhydroisoquinoline, 5,6-dipropoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline and 5-methoxy-6-ethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
• alkanoyl halides and aryl substituted alkanoyl halides which can be used in the first step of the process are acetyl chloride, propionyl chloride, butyryl bromide, benzoyl chloride, p-methoxybenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, diphenylacetyl chloride, diphenylpropionyl bromide, 3,4-dimethoxyphenylacetyl chloride, 4-methylbenzoyl chloride, 4-fluorophenylacetyl chloride and 3,4-diethoxybenzoyl chloride.
• Reaction between the tetrahydroisoquinoline and alkanoyl halide, or aryl-substituted alkanoyl halide, to form the desired amide is readily effected by bringing the reactants together in an inert liquid reaction medium, such as benzene or toluene, in the presence of an acid binding agent, such as triethylamine. Heating of the mixture, such as at reflux temperature, increases the reaction rate. After the reaction is terminated the amide reaction product can be isolated from the reaction mixture by conventional procedures.
• amides which can be produced as described from the appropriate reactants are N-acetyl-5,6-dimethoxycyclopentao[h]-1,2,3,4-tetrahydroisoquinoline, N-propionyl-5,6-diethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-(3,4-dimethoxybenzoyl)-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-(3,4-dimethoxyphenylacetyl)-5,6-dimethoxycyclopentao[h]-1,2,3,4-tetrahydroisoquinoline, N-(diphenylacetyl)-5,6-dimetoxycyclopentao[h]-1,2,3,4-tetrahydroisoquinoline, N-(4-fluorophenylacetyl)-5,6-dimethoxy
• the amides can be readily reduced chemically to the tertiary amine compounds of Formula 2 where R 4 has at least 2 carbon atoms.
• Chemical reduction of the amides can be effected by use of a suitable reducing agent, such as lithium aluminum hydride in anhydrous ether at a temperature which increases the reaction rate, such as the reflux temperature.
• a suitable reducing agent such as lithium aluminum hydride in anhydrous ether at a temperature which increases the reaction rate, such as the reflux temperature.
• the resulting tertiary amine can be recovered and isolated as an acid addition salt using standard techniques.
• tertiary amines which can be produced as described are N-ethyl-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-propyl-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-phenylethyl-5,6-diethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-benzyl-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-(3,4-dimethoxybenzyl)-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-(3,4,5-trimethoxyphenylethyl)-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetra
• the compounds of Formula 2 in which R 4 is methyl can be prepared by reacting the secondary amines previously named above with formic acid and formaldehyde at an elevated temperature according to the standard procedures for methylating secondary amines to tertiary amines by this process.
• Some of the tertiary amines which are produced in this way are N-methyl-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-methyl-5,6-diethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline and N-methyl-5,6-dipropoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
• a second method of making the compounds of Formula 2 is to react the secondary amine starting materials with an appropriate aldehyde to form an intermediate imine or Schiff's base which can then be reduced catalytically with hydrogen at a moderate pressure and moderately elevated temperature.
• This process can be represented as follows: ##SPC5##
• R 3 , R 5 , R 6 and R 7 have the previously assigned significance.
• aldehydes which can be used in this process are acetaldehyde, propionaldehyde, butyraldehyde, benzaldehyde, 3,4-dimethoxybenzaldehyde, phenylacetaldehyde, diphenylacetaldehyde, p-chlorobenzaldehyde, ⁇ , ⁇ , ⁇ -trifluoropropionaldehyde, 3,5-dimethylbenzaldehyde and ⁇ -phenylpropionaldehyde.
• Some of the Schiff's bases or imines which are produced as intermediates in the described process are N-ethylidene-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-propylidene-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-benzylidene-5,6-diethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-phenylethylidene-5,6-dipropoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline and N-diphenylethylidene-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydoisoquinoline.
• Reduction of the intermediate imines can be readily effected by catalytic hydrogenation at moderate pressures using platinum oxide or palladium as the catalyst and a suitable liquid carrier such as glacial acetic acid at room temperature or a moderately elevated temperature such as up to 50°C.
• a suitable liquid carrier such as glacial acetic acid at room temperature or a moderately elevated temperature such as up to 50°C.
• the reaction mixture can be handled in a conventional way to isolate the desired tertiary amine.
• Tertiary amines such as those previously named herein can be produced by this process.
• the tertiary amines provided by this invention having 5,6-dialkoxy substituents can be converted to the corresponding 5,6-dihydroxy compounds by use of concentrated hydrogen bromide or hydrogen iodide in water or acetic acid solution to cleave the ether linkages. It is preferred to use 48% hydrogen bromide in water for this cleavage.
• the reaction proceeds readily at an elevated temperature, and preferably the reflux temperature.
• the process can be represented as follows: ##SPC6##
• Some of the compounds which can be produced by cleavage of the alkoxy groups from the 5,6-positions are N-ethyl-5,6-dihydroxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-propyl-5,6-dihydroxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-phenylethyl-5,6-dihydroxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-benzyl-5,6-dihydroxycyclopentano[h]-tetrahydroisoquinoline, N-(3,4-dimethoxybenzyl)-5,6-dihydroxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-(3,4,5-trimethoxyphenylethyl)-5,6-dihydroxycyclopentano[h]-1,2,3,4-t
• N-substituted -5,6-dihydroxycyclopentano[h]-1,2,3,4-tetrahydroisoquinolines can be converted to esters by reaction with suitable esterifying agents such as alkanoic acid anhydrides, alkanoyl halides, alkanoic acids and aralkanoyl halides.
• suitable esterifying agents such as alkanoic acid anhydrides, alkanoyl halides, alkanoic acids and aralkanoyl halides.
• R 3 and R 4 have the previously assigned significance and R 8 is a lower alkyl or aryl-lower alkyl group.
• esters which can be produced from the otherwise corresponding 5,6-dihydroxy compounds are N-methyl-5,6-diacetoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-propyl-5,6-dipropionyloxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline, N-benzyl-5,6-dibenzoyloxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline and N-diphenylethyl-5,6-diphenylacetoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline.
• the tertiary amines of this invention can be converted to acid addition salts by contacting the amines with a suitable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid or an organic acid such as citric acid, acetic acid, formic acid, malic acid, fumaric acid, succinic acid, benzoic acid and tartaric acid.
• a suitable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid
• an organic acid such as citric acid, acetic acid, formic acid, malic acid, fumaric acid, succinic acid, benzoic acid and tartaric acid.
• Quaternary ammonium salts of the compounds are readily prepared by contacting the compounds with an alkyl halide or an alkyl sulfate, aralkyl halide or arakyl sulfate such as methyl chloride, ethyl bromide, propyl iodide, benzyl chloride, benzyl sulfate and methyl sulfate as well as other compounds known to form quaternary ammonium salts with tertiary amines.
• an alkyl halide or an alkyl sulfate, aralkyl halide or arakyl sulfate such as methyl chloride, ethyl bromide, propyl iodide, benzyl chloride, benzyl sulfate and methyl sulfate.
• tertiary amines of this invention are useful as neutralizing agents since they are bases which form salts with acids.
• the compounds are also useful pharmaceutically. These compounds as the base or acid addition salt when administered to animals parenterally or orally exert an anti-hypertensive effect.
• the compounds thus can be used to reduce blood pressure.
• N-methyl-5,6-dihydroxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline has an ALD 50 in mice of 160-200 mg/kg i.p. When administered at 50 mg/kg i.p. to hypertensive rats the following percent change in systolic blood pressure was observed:
• N-(2-methylbutyl)-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline has an ALD 50 in mice of 178-200 mg/kg i.p. when administered in water. When administered at 25 mg/kg i.p. in water to hypertensive rats the following percent change in systolic blood pressure was observed:
• N-(3,4-dimethoxybenzoyl)-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline has an ALD 50 greater than 1000 mg/kg i.p. when adminstered to mice as a suspension in 1% tragacanth. When administered at 100 mg/kg i.p. as a suspension in 1% tragacanth to hypertensive rats the following percent change in systolic blood pressure was observed:
• N-(3,4-dimethoxybenzyl)-5,6-dimethoxycyclopentano[h]-1,2,3,4-tetrahydroisoquinoline has an ALD 50 of 200-250 mg/kg i.p. in mice as a suspension in 1% tragacanth.
• ALD 50 200-250 mg/kg i.p. in mice as a suspension in 1% tragacanth.
• the amount of active ingredient administered may be varied; however, it is necessary that the amount of active ingredient be such that a suitable dosage is given.
• the selected dosage depends upon the desired therapeutic effect and on the duration of treatment. Dosages of from 0.1 to 25 mg/kg of body weight daily, preferably in divided doses, i.e., three to four times daily, can be administered.
• the active agents of this invention can be administered to animals, including humans, as pure compounds. It is advisable, however, to first combine one or more of the compounds with a suitable pharmaceutical carrier to attain a satisfactory size to dosage relationship and thereby obtain a pharmaceutical composition.
• Pharmacuetical carriers which are liquid or solid can be used.
• Solid carriers such as starch, sugar, talc and the like can be used to form powders.
• the powders can be used for direct administered or they may be used to make tablets or to fill gelatin capsules.
• Suitable lubricants like magnesium stearate, binders such as gelatin, and distintegrating agents like sodium carbonate in combination with citric acid can be used to form tablets.
• Sweetening and flavoring agents can also be included.
• Unit dosage forms such as tablets and capsules can contain any suitable predetermined amount of one or more of the active agents, and they may be administered one or more at a time at regular intervals. Such unit dosage forms, however, should generally contain a concentration of 0.1 to 50 percent by weight of one or more of the active compounds. Unit dosage forms, such as tablets and capsules, can contain about 2 to 300 mg of active agent.
• a typical tablet can have the composition:
• the compounds exhibit both oral and parenteral activity and accordingly they can be formulated in dosage forms for either oral or parenteral administration to a patient.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, granules and the like.
• Liquid dosage forms for oral administration include emulsions, solutions, suspensions, syrups and the like, containing diluents commonly used in the art such as water. Besides inert diluents, such preparations can also include adjuvants such as wetting agents, emulsifying and suspending agents and sweetening, flavoring and perfuming agents.
• Preparations for parenteral administration include sterile aqueous or non-aqueous solutions.
• non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
• the parenteral preparations are sterilized by conventional methods.
• R 5 and R 6 have the previously assigned significance.
• Reduction of the 4,5-dialkoxy-1-indanone can be readily achieved catalytically using hydrogen and a suitable catalyst such as palladium.
• the hydrogenation is effected by placing the starting material in glacial acetic acid containing the catalyst and a small amount of concentrated hydrochloric acid. The hydrogenation proceeds readily at room temperature using a hydrogen pressure of about 25 to 100 psig. After hydrogen uptake has ceased the product can be recovered from the reaction mixture by conventional methods.
• 4,5-dialkoxyindanes which can be produced as described are 4,5-dimethoxyindane, 4,5-diethoxyindane, 4,5-dipropoxyindane, 4,5-diisopropoxyindane, 4,5-dibutoxyindane and 4-methoxy-5-ethoxyindane.
• a mixture of 4,5-dimethoxy-6- and -7- indanaldehydes formed by the described procedure contains about 75% of the 7-formyl and 25% of the 6-formyl isomers. Obviously, the presence of other alkoxy groups than the methoxy group could lead to different amounts of the isomers in the relating mixture.
• the isomeric mixture of aldehydes obtained by the described process is generally a liquid. Residual amounts of solvent are removed from the liquid by distillation following which the product is distilled under high vacuum to give a pure liquid mixture. Upon cooling, one of the isomeric aldehydes crystallizes from the liquid and is removed by filtration. Thus, 4,5-dimethoxy-7-indanaldehyde crystallizes and leaves a liquid which is primarily 4,5-dimethoxy-6-indanaldehyde. Fractional distillation of the liquid gives the pure 6-formyl isomer.
• the 5,6-dialkoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinolines used as starting materials are prepared from 4,5-dialkoxy-6-indanaldehydes by reacting the aldehyde with a 1-nitroalkane to produce a 4,5-dialkoxy-6-nitrovinylindane, chemically reducing the nitrovinyl compound to the corresponding aminoalkyl compound, reacting the resulting amine with formaldehyde to produce a Schiff's base and then treating the Schiff's base with acid to effect a Pictet-Spengler acid catalyzed ring closure.
• This series of reactions can be represented as follows: ##SPC10##
• R 3 , R 5 and R 6 have the previously assigned meaning.
• nitromethane, nitroethane, 1-nitropropane and other such 1-nitroalkanes can be used.
• Condensation of the 4,5-dialkoxy-6-indanaldehyde with the nitroalkane can be readily effected by procedures disclosed in Gairaud et al., J. Org. Chem., 18, 1 (1953) and particularly by the use of ammonium acetate in glacial acetic acid at an elevated temperature. After cooling the reaction mixture, the desired 4,5-dialkoxy-6-nitrovinylindane crystallizes from solution and is separated by filtration.
• the 4,5-dialkoxy-6-nitrovinylindanes are readily reduced chemically by means of lithium aluminum hydride in dry ether according to the method of Marchant et al., J. Chem. Soc., 327 (1956) to produce the desired 4,5-dialkoxy-6-aminoethylindanes.
• Some of the compounds which are produced in this way are 4,5-dimethoxy-6-aminoethylindane, 4,5-diethoxy-6-(2-aminopropyl)indane, 4,5-dipropoxy-6-(2-aminobutyl)indane and 4-methoxy-5-ethoxy-6-aminoethylindane.
• the 4,5-dialkoxy-6-aminoethylindanes are converted to the Schiff's bases by reaction with formaldehyde using conventional reaction conditions for preparing Schiff's bases.
• some of the compounds so produced are N-methylidene-4,5-dimethoxy-6-(2-aminoethyl)indane, N-methylidene-4,5-diethoxy-6-(2-aminopropyl)indane, N-methylidene-4,5-dipropoxy-6-(2-aminobutyl)indane and N-methylidene-4-methoxy-5-ethoxy-6-(2-aminoethyl)indane.
• the described Schiff's bases are readily cyclized in aqueous acid, such as 23% hydrochloric acid, at a moderately elevated temperature of about 40° to 75°C., to the cyclopentano[h]1,2,3,4-tetrahydroisoquinolines.
• aqueous acid such as 23% hydrochloric acid
• the product is readily recovered by evaporation of the solvent and acid.
• Representative cyclopentano[h]1,2,3,4-tetrahydroisoquinolines which are produced as described are 5,6-dimethoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinoline, 5,6-diethoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinoline, 5,6-dipropoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinoline and 5-methoxy-6-ethoxy-cyclopentano[h]1,2,3,4-tetrahydroisoquinoline.
• the compound was eluted with 500 ml of benzene, 200 ml of 75:25 benzene:chloroform, 1100 ml of 50:50 benzene: chloroform and 800 ml of 25:75 benzene:chloroform.
• the material which came off the column in the 50:50 chloroform:benzene fraction was combined, boiled with activated charcoal in 90°-120°C. ligroine, filtered, and reduced in volume.
• the amide crystallized as a powder.
• Another recrystallization gave 1.253 g (39%) of white powder, m.p. 106°-108° C.
• the pecipitate was extracted with ether and the ether was evaporated giving an oil which solidified.
• the solid was recrystallized twice from 90-120°C. ligroine yielding 176 mg (12%) of slightly orange prisms, m.p. 127°-128.5°C.
• the solution was refluxed for 6 hours, cooled and the reaction mixture was poured over 200 ml of ice and water (ether and salt were added at this point to increase the volume of the organic phase, to invert the two layers and to break emulsions).
• the organic phase was washed with 2 ⁇ 100 ml of 8% NaHCO 3 solution, 1 ⁇ 100 ml of water and dried over Na 2 SO 4 .
• the mixture of aldehyde isomers was distilled under high vacuum (b.p. 115°-126°C; 0.28 mm) giving 10.2 g of the 6- and 7-position aldehydes (88%).
• the 7-position aldehyde which crystallized from the liquid was filtered. This process was repeated several times by seeding the filtrate followed by cooling.
• the 4,5-dimethoxy-6-indanaldehyde was obtained by high vacuum (20-50 ⁇ ) fractional distillation of the mixture of aldehydes remaining after repeated crystallization and filtering off of the 7-aldehyde.
• the 6-aldehyde distilled as a pure substance in the first fractions followed by a mixture of the aldehydes and finally the pure 7-aldehyde.
• the 4,5-dimethoxy-6-indanaldehyde was a liquid at room temperature but crystallized when refrigerated. An approximate m.p. (11°C) was obtained from the temperature of a mixture of the solid in equilibrium with the liquid.
• N-methylidene-4,5-dimethoxy-6-(2-aminoethyl)indane weighed 8.72 g and was dissolved in 39 ml of 23% HCl followed by heating at 50°-60°C for 30 minutes.
• the aqueous acid was removed on a rotary evaporator yielding an oily, viscous substance which was dried in a vacuum oven in the presence of P 2 O 5 .
• a tacky hygroscopic solid was obtained which was crystallized from ether-ethanol giving fine needles, m.p. 215.5°-216.5°C. Further experimentation showed acetonitrile-ethanol to be a better recrystallization solvent.

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Citations (6)

• 1974
  • 1974-03-28 US US05/455,671 patent/US3962254A/en not_active Expired - Lifetime
• 1975
  • 1975-03-12 IL IL46814A patent/IL46814A0/xx unknown
  • 1975-03-18 GB GB11309/75A patent/GB1509302A/en not_active Expired
  • 1975-03-21 DE DE19752512390 patent/DE2512390A1/de active Pending
  • 1975-03-21 DK DK120875A patent/DK120875A/da unknown
  • 1975-03-27 BE BE154859A patent/BE827285A/xx unknown
  • 1975-03-27 CA CA223,275A patent/CA1061790A/en not_active Expired
  • 1975-03-27 FR FR7509665A patent/FR2265380B1/fr not_active Expired
  • 1975-03-27 NL NL7503708A patent/NL7503708A/xx not_active Application Discontinuation

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